IL-1β Stimulates Brain-Derived Neurotrophic Factor Production in Eutopic Endometriosis Stromal Cell Cultures

Abstract

Endometriosis implants are comprised of glandular and stromal elements, macrophages, nerves, and blood vessels and are commonly accompanied by pelvic pain. We propose that activated macrophages are recruited to and infiltrate nascent lesions, where they secrete proinflammatory cytokines, promoting the production of chemokines, neurotrophins, and angiogenic growth factors that sustain an inflammatory microenvironment. Immunohistochemical evaluation of endometriosis lesions reveals in situ colocalization of concentrated macrophages, brain-derived neurotrophic factor (BDNF), and nerve fibers. These observations were coupled with biochemical analyses of primary eutopic endometriosis stromal cell (EESC) cultures, which allowed defining potential pathways leading to the neuroangiogenic phenotype of these lesions. Our findings indicate that IL-1β potently (EC = 7 ± 2 ng/mL) stimulates production of EESC BDNF at the mRNA and protein levels in an IL-1 receptor-dependent fashion. Selective kinase inhibitors demonstrate that this IL-1β effect is mediated by c-Jun N-terminal kinase (JNK), NF-κB, and mechanistic target of rapamycin signal transduction pathways. IL-1β regulation of regulated on activation normal T cell expressed and secreted (RANTES), a prominent EESC chemokine, also relies on JNK and NF-κB. An important clinical implication of the study is that interference with BDNF and RANTES production, by selectively targeting the JNK and NF-κB cascades, may offer a tractable therapeutic strategy to mitigate the pain and inflammation associated with endometriosis.

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

“…IL-1β also contributes to recruitment of macrophages and neuroangiogenesis by regulating chemokine RANTES and promoting the production of brain-derived neurotrophic factor (BDNF), which co-localizes with macrophages and nerve fibers in endometriotic lesions and cultures of eutopic stromal cells; both events are mediated through c-Jun N-terminal kinase (JNK) and NF-κB signaling pathways. These findings support the notion of interaction between pro-inflammatory factors that favor the communication between different cell types in endometriotic lesions, which as a result promote the recruitment of vessels and nerves to stimulate angiogenesis, growth of the lesion, and generation of pain (40).…”

“…Inflammation in endometriosis is generally attributed to the recruitment of macrophages and other activated leukocytes from bone marrow to the developing endometriotic lesions and eutopic endometrium, these cells are attracted by chemokines synthesized and released in situ. In the endometriotic lesions, immune cells secrete elevated levels of pro-inflammatory cytokines, which in turn stimulate the production of diverse molecules such as chemokines, and growth factors that sustain an inflammatory microenvironment and the remodeling of the ectopic tissue (40). This tissue also has the capacity of releasing pro-inflammatory factors, creating a positive feedback loop that maintains the chronic inflammation state (57).…”

“…Neurogenesis is linked to both inflammatory response and angiogenesis and, along with an imbalance in sensory and sympathetic innervation, contributes to the growth of nerve fibers, subsequent peripheral neuroinflammation, and generation of chronic pain (39). One of the postulated consequences of immune cell activation in the endometriosis microenvironment is the production of cytokines, growth factors, and eicosanoids that simultaneously stimulate lesion innervation and neovascularization through a coordinated mechanism that is known as neuroangiogenesis (40).…”

Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis

“…In these diseases and gout, IL-1 is an important factor causing strong pain. Indeed, recently Yu et al reported that a potential of IL-1β in neuroangiogenesis by the induction of brain-derived neurotrophic factor from eutopic endometriosis stromal cells (8). Suppression of IL-1 may provide effective treatment against pelvic pain caused by endometriosis.…”

“…However, because the reflux of menstrual blood is observed in most women, endometriosis cannot be explained by reflux alone. In addition, inflammatory cytokines, such as tumor necrosis factor α (5, 6), interleukin (IL)-1β (7, 8), and IL-33 (9), and immune cells, such as macrophages (10) and natural killer cells (11, 12), were reported to be involved in the pathogenesis of endometriosis. However, limited studies have investigated the mechanism of their actions in endometriosis.…”